N-alkyl-n-(alkylated-benzyl)dihaloacetamides and preparation thereof



Unite N ALKYL N (ALKYLATED BENZYL)DIHALO- ACETAM'IDES ANDPREPARATION'THEREOF No Drawing. Application December9, 1955 A,

Serial No. 551,999

9 Claims. (Cl. 260-562) This invention relates to novelN-alkyl-N-(alkylatedbenzyl)dihaloacetamides, to their preparation, andto amebicidal compositions containing these compounds as activeingredients thereof.

During and since World War H, it has become increasingly apparent thatamebiasis is even more serious a problem than had been previouslyassumed. This realization has stimulated the search for new drugseffective in treating this debilitating disease. The search has beendirected toward finding highly effective, non-toxic, nonmetallic andrelatively inexpensive remedies to improve on the presently availableand only limitedly useful drugs such as carbasone, chiniofon,diiodohydroxyquinoline and emetine bismuth iodine. Other workersrecently have found the relatively new chlortetracycline andoxytetracycline to be highly effective; however, these antibioticssuffer the disadvantages of being relatively expensive and, when testedin hamsters, of producing marked bloating of the cecum and altering thececal flora. It is well known that these antibiotics also oftenadversely disturb and alter the intestinal flora in human patientsbecause of their broad antibacterial spectrum. In contrast, my newcompounds have very slight if any antibacterial activity States Patentand can be expected therefore to have little if any effect on the normalintestinal flora. I

My search has resulted in the compounds of the instant invention, thesecompounds having the general formula C O OH(halogen)2 where Ar is aphenyl radical substituted by from one to three lower alkyl radicals,and R is a lower alkyl radical.

These compounds not only have markedly high amebacidal activities asevidenced by cure of hamsters infected with amebiasis, but alsosurprisingly low toxicities. Moreover, they have a novel and relativelysimple chemical structure that does not resemble and is not suggested byany amebicidal agent known prior to my work in this field. My newcompounds of course vary among themselves in magnitude of amebicidalactivity, but even the less active embodiments are from three to fourtimes more active than the commercial amebicidal agents, chiniofon anddiiodohydroxyquinoline, while the more active embodiments are from about10 to 20 times more active than these two commercial quinolineamebicides;

and from about 2 to 3 times more active than carbasone had prepared thiscompoundas a possible intermediate;

2,862,967 Patented Dec. 2, 1958 however, they failed in all attempts toconvert it into an isoquinoline derivative. Thus, they found no utilityfor this compound and it was completely neglected until, in

the course of my search for new amebicidal composi- .;less active thanthe most active embodiments of the instant application but, at the sametime, being considerably more active than chiniofon anddiiodohydroxyquinoline and more active than carbasone.

In the above formula for my new compounds, the alkyl substituents of thephenyl radical designated by Ar can be in any of the available positionsof the phenyl nucleus, and have from one to six carbon atoms, includingsuch substituents as: methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, 2-butyl, n-pentyl, n-hexyl, and the like. Preferredembodiments of the compounds of my invention are those with at least onealkyl substituent having from three to six carbon atoms.

The lower alkyl radical of the above general formula, designated as R,has preferably from one to six carbon atoms and includes such examplesas methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, l-butyl,n-pentyl, B-methylbutyl, n-hexyl, Z-methylpentyl, and the like.

The halogen atoms of the dihaloacetyl radicals of my compounds,designated in the above formula as -COCH(halogen) can be chloro, bromo,iodo or fluoro, such dihaloacetyl radicals including dichloroacetyl,dibromoacetyl, diiodoacetyl, difluoroacetyl, bromochloroacetyl,bromiodoacetyl, and the like.

The compounds of my invention were prepared by treating an N-(loweralkyl)-alkylatedbenzylamine of the formula, Ar-Cl-hNh-R, with adihaloacetyl hal ide, where Ar and R have the meanings given above. Thehalo radical attached to the carbonyl function, was preferably chloro;however, other halo radicals, i. e., bromo, iodo, fluoro, also can beused. Illustrations of the process of my invention are: the preparationof N-isopropyl N (2,4,6 trimethylbenzyl)dichloroacetamide by' treatingN-isopropyl-2,4,6-trirnethylbenzylamine with dichloroacetyl chloride;the preparation of N-isobumethyl Were prepared also by reacting anN-methyl-,

alkylated-benzylamine, Ar-CH NHCH with a lower alkyl dihaloacetate, e.g., methyl dichloroacetate, where the lower alkyl portion of thisintermediate ester has from one to six carbon atoms. Illustrations ofthis modification of my process are: the preparation of N-methyl-N-(2,4-diisopropylbenzyl)dichloroacetamide by reacting N-methyl-Z,4-diisopropylbenzylamine with methyl dichloroacetate; and thepreparation of N-methyl-N-(4-n-butylbenzyl) dibromoacetamide by reactingN-methyl-4-n butyl- V benzylamine With ethyl dibromoacetate. Thereaction was run by mixing the reactants and allowing them to stand fromabout one to four days at room temperature or by heating the reactionmixture for shorter periods (such as about 12 to 18 hours) at anelevated temperature (such as 45 to 0.). I found that N-(loweralkyl)-alkylatedbenzylamines where the lower alkyl radical is largerthan methyl would not undergo the reaction with the lower alkyldihaloacetates to form the corresponding disubstituteddihaloacet'amides.

The intermediate N-(lower alkyl)-alkylated-benzylamines were preparedeither by treating an allcylated: ben'zaldehyde of the. formula ArCHOwith. an alkylainiine of the formula RNH followed by catalytic.reduction of the anil, ArCH=N-R, or by treating an alkyl'a'ted-benzylhalide, ArCH halogen, with an, alkylarnine, RN H Illustrations ofthesetwo procedures for preparingthe in.

termediate N-(lower alkyl)-alkylated-benzylarnines are given,respectively, as-followsz the'preparationofN-isopropyl-2,4,6-tr'irnetliylbenzylamine by; treating 2,4,6-tri;methylbenzal'dehyde with isopropylamineto forrfrthe an'il which is thencatalyti'cally reduced; the-fonna'tion'or N-Qisoprcpyl-4-n-butylbeniylamine by treating 4-n-butylrminutes and thendissolved in 125 ml. of ethanol and reduced catalytically withpalladium-on-charcoal catalyst. After the catalyst had been filteredoff, the filtrate was fraetionally distilled, yielding 16.5 g. ofN-isoprd pyl-4-isopropylbenzylamine, B. P. 82-85 C. at 0.65 mm;, n1.4968.

Analysis.--Calcd. for C H N: N, 7.34. Found: N, 6.96.

Other N-(lower alkyl)-alkylbenzylamines prepared by the above procedure,using the appropriate alkylbenzaldehyde and lower alkylamine, are givenin the following paragraphs:

N-isopropyl-4-methylbenzylamine (19 g.), B. P. 55- 57 C. at 0.5 mm., n1.4990, prepared from 24 g. of 4- methylbenzalclehyde and 12 g-.. ofisopropyla'mine. Analysis.Calcd. for C H N: N, 8.59; Found: N, 8.52.

N-methyl-4-methylbenzylamine (9.2 g..), B. P. 92-94' C. at 15 mm., 111.5162, prepared from 18 g. of 4-rnethylbenzylaldehyde' and 125- ml. of20% methanolic methylamine (0.7 mole). Analysis.-Calcd. for C H N: N,10.36. Found: N, 10.21.

N-methyl-3-methylbenzylamine (14.8 g.), B. P. 9092 C. at 15 mm., 111.5170, prepared from 18 g. of- 3- methylbenzaldehyde and 125 ml. of 20%methanolic methlyamine (0.7 mole). AnaIysis.--Calcd. for C I-I N: N,10.36. Found: N, 10.22.

N-methyl-4isopropylbenzylarnine (35 g.) B. P. 102 107 C. at 15 mm.,prepared from 65 g. of 4-isopropylbenzaldehyde-and 155 ml. of 26.8%methanolic methylarnine. AnnIysis.-Calcd. for C H N-z N, 8.60. Found: N,8.42.

Other N-(lower alkyl)-alkylated-benzylamines can be B. N-(lower alkyl)N- (alkylated-benzyl) dihalocetamides The preparation of these compoundsusing a dihaloacetyl halide is illustrated by the following preparationof N-isopropyl N (4-isopropylbenzyl)dichloroacetamide:

12.5 g. of dichloroacetylchloride was added dropwise with stirring at 0C. to a mixture of 16 g. of N-isopropyl-4-isopropylbenzylamine, 150 ml.of ethylene dichloride and 84 ml. of 1 N sodium hydroxide solution.

4 The mixture was allowed to warm up to room temperalife and stirringwas continued for one hour. The organic layer was separated, washed with1 N hydrochloric acid, then water, and dried. The ethylene dichloridewas removed by distillation and the product, N-iscpropyl-N-(4-isopropylbenzyl)dichloroacetamide, was obtained by distillationinvacuo, B. P. 125-130 C. at 0.05 mm.

A-nalysis.-Calcd. for C H Cl NO: C, 59.61; H, 7.00; CI, 23.50.

Found: C, 59.70; H, 7.12; Cl. 23.53.

When the above procedure is followed by using diiodoacetyl iodide,dibromoacetyl bromide, difiuoroacetyl fluoride or bromochloroacetylchloride in place of dichloroacetyl chloride, the following respectivecompounds result: N-is opropyl-N- (4-isopropylbenzyl) diidoacetamide,N-isopropyl-N-(4-isopropylbenzyl) dibromoacetamide, N-isopropyl-N-(4-isopropylbenzyl)difluoroacetamide or N- isopropyl-N-(4-isopropylbenzyl) bromochloroacetamide.

Other N-(lower. alkyl) N (alkylbenzyl)dichloroacetairiides carrbevprepared according to. the procedure given above using the appropriatereactants; such compounds include Nisopropyl-N-( 3 ,4-diisopropylbenzyldichloroacetamide, N-rnethyl N (4-n-hexylbenzyl)dichloroacetamide,N-isobutyl N (4 isobutylbenzyl)dichloroacetamide, N- 2'-methy1butyl -N-(.2',4,6-trimethylbenzyl dichloroace'tamide, N-(n-hexyl)-N-(3,4diethylbenzyl)dichloroacetamide, and the like.

7 EXAMPLE. 2 N-mejthyl-N-( i isopropylbeizzyl)a ichloroacetamide Thiscompound was prepared by reacting N;-methyl-4:-isopropylbenzylaminewitheither (A) dichloroacetyl. chlorideor (B) methyldichloroacetate.

A. This preparation was carried outfollowing the procedure described inExample 1B using 16.3 g. of N-methyl-4-isopropylbenzylamine, ml.. ofethylene dichloride, 100 ml. of 1N sodium hydroxide solution and 16.2 g.of dichloroacetyl chloride. The resulting product,N-methyl-N-(4-isopropy1benzyl)dichloroacetamide, melted at 49.1-50.8 C.(corn) when recrystallized from nhexane.

Analysis.Calcd. for C H CI NO: C, 56.94; H, 6.25; C1,; 25.86. Found: C,57.13;.H, 5.68; Cl, 25.30.

B. A mixture of 8.l.-5,g.'of N-methyl-4 isopropylbenzyl-.

amine and 7.3 g. of methyl dichloroacetate was allowed to stand at roomtemperature for twenty-four hours. The reaction mixture was thendissolved in benzene and washed several times with 1N hydrochloric acid,water,

2.5% aqueous sodium hydroxide solution and, finally,

water; The benzene; solution was dried over anhydrous calcium sulfateandthe benzene was removed by distillation; to give 9.5 g. ofN'-methyl-N-.(4-isopropylbenzyl)- dichloroacetamide. This product isidentical with the compoundobtainedfollowing the procedure of Example2A, as determined by'a mixed melting. point.

7 EXAMPLE 3 N '-me'thyl-N-(4-methylbenzyl-)-dich loroaceram ide EXAMPLE..4

1N-n z'ethyl-N-(Sorzeflrylbefizyl) dichloroacetamide This; preparationwas carried out following the procedure described in Example 2B using 12g. of, N-Iriethyl- 3-methylbe'n-zylamine' and 13'-g. of methyldichloroacetate allowing the reactants" to stand at room temperature forthree days. The product, N-methyl-N-(3-methylbenzyl)- dichloroacetamide,was obtained by distillation invacuo, B. P. 128 C. at 0.4 mm., n 1.5514.n standing this product solidified, M. P. 37.0-40.2 C. (corn) whenrecrystallized from n-hexane.

Analysis-Calm. for C H Cl NO: C, 53.69; H, 5.32; Cl, 28.81. Found: C,53.38; H, 5.56; Cl, 29.18.

EXAMPLE N-isopropyZ-n-(4-methylbenzyl) dichloroacetamide Thispreparation was carried out following the procedure described in Example1B using 8.1 g. of N-isopropyl- 4-methylbenzylamine, 100 ml. of ethylenedichloride, 50 ml. of 1N sodium hydroxide solution and 7.3 g. ofdichloroacetyl chloride in 20 ml. of ethylene dichloride. There was thusobtained the product, N-isopropyl-N-(4- methylbenzyl)dichloroacetamide,B. P. 120 C. at 0.05 mm.

Analysis.-Calcd. for C H Cl NO: C, 56.90; H, 6.26; Cl, 25.90. Found: C,57.35; H, 6.26; Cl, 25.99.

The N-(lower alkyl)-N-(alkylated-benzyl)dihaloacetamides of theforegoing examples when administered orally in aqueous suspension tohamsters infected with Endamoeba criceti were found to completely clearthe animals of the infection at drug levels below 100 mg. per kg. ofbody weight. Some of the compounds, for instance, N-methyl-N-(4-isopropylbenzyl)dichloroacetamide and N- isopropyl N (4isopropylbenzyl)dichloroacetamide have ED values in the range between 16and 20 mg. per kg. of body Weight, ED meaning the eifective dosenecessary to clear 50% of the hamsters of the amebic infection. Coupledwith this high activity, my compounds have very low toxicities. Forexample, N-methyl-N-(4- isopropylbenzyl)dichloroacetamide has an acuteoral ALD (mice; 7-day) of 5335 mg. per kg.

For purposes of comparison, the amebicidal activities (in terms of EDvalues determined as outlined above) of available drugs of commerce aregiven as follows: chiniofon, 286 mg. per kg.; diiodohydroxyquinoline,235 mg. per kg.; carbasone, 45 mg. per kg.; chlortetracycline, 22.9 mg.per kg.; and oxytetracycline, 8.75 mg. per kg.

For practical medication, my newN-alkyl-N-(alkylated-benzyl-dihaloacetamides are best administeredorally in solid form with the aid of a carrier. Thus, the compounds canbe formulated in unit dosage form as tablets in combination with anadjuvant such as one or more of the following: calcium carbonate,starch, gelatin, talc, magnesium stearate, acacia, and the like, oralternatively, they can be employed in capsule form either alone oradmixed with an adjuvant. My compounds can also be advantageouslycombined with other amebicides such as chloroquine when desired.Illustrative of a tablet formulation of my compounds is one weighing 660mg. and containing 500 mg. of N-isopropyl-N-(4-isopropylbenzyl)-dichloroacetamide, 25 mg. of calcium carbonate as a diluent, 90 mg. ofstarch as a disintegrator, 30 mg. of gelatin as a binder and 15 mg. oftalcum as a lubricant. Illustrative of a capsule formulation is onecontaining 500 mg. of N-methyl-N-(4-isopropylbenzyl)dichloraocetamide,40 mg. of starch and 10 mg. of talcum. Other tablet and capsuleformations can be made varying the quantiwhere n is an integer from 1 to3 and R is a lower alkyl radical.

2. An N-alkyl-N-(monoalkylbenzyl)dihaloacetamide having the formula (1lk '1 R owara 3 -CHz-N C O OH (halogen) z where R is a lower alkylradical.

3. An N-alkyl-N-(monoalkylbenzyl)dihaloacetamide having the formula(lower alkyl) C HzN o 0 OH a o where the lower alkyl substituent of thephenyl nucleus has from three to six carbon atoms, and R is a loweralkyl radical.

4. An N-alkyl-N-(monoalkylbenzyl)dichloroacetamide having the formula(lower alkyl) R GOCHOlz where the lower alkyl substituent of the phenylnucleus has from three to six carbon atoms, and R is a lower alkylradical.

5. N-methyl-N-(4-isopropylbenzyl)dichloroacetamide.

6. N isopropyl N (4 isopropylbenzyl)dichloroacetamide.

7. N-methyl-N-(4-methylbenzyl)dichloroacetamide.

8. N-methyl-N-(3-methylbenzyl)dichloroacetamide.

9. N-isopropyl-N-(4-methylbenzyl)dichloroacetamide.

References Cited in the file of this patent UNITED STATES PATENTSCassell et al Sept. 25, 1951 Surrey Jan. 24, 1956 OTHER REFERENCESMannich et al.; Archiv. der Pharm.," vol. 250 (1912), pp. 546, 544.

Isshiki et al.: J. Pharm. Soc. Japan, vol. 72 (1952), pp. 72-73.

Kushner et al.: J. Org. Chem, vol. 16 (1951), pp. 1273-88.

Rebstock et al.: I. Am. Chem. Soc., vol. 73 (1951), page 3670.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.2,862,967 December 2, 1958 Alexander R Surrey It is hereby certifiedthat error appears in the printed specification of the above numberedpatent requiring correction and that the said Letters Patent should readas corrected below.

Column 1, line 28, and column 2, line 48, for "iodine", in eachoccurrence, read iodide column 2, line 25, for "l-butyl" read 2-butylcolumn 4, line ll, for "followed by" read followed but line 15, for"diidoace'tamide" read diiodoacetamide line 67, for "Cl,28.2l" read01,263.81 column 5, line 42, for "8.75 mg. per kg." read 18.75 mg. perkg, line 62, for "formations" read formulations Signed and sealed this21st day of April 1959.

(SEAL) Attest:

KARL H. AXLINE ROBERT C. WATSON Attesting Officer Commissioner ofPatents

1. AN N-ALKYL-N-(ALKYLBENZY)DIHALOACETAMIDE HAVING THE FORMULA